Pathophysiology of Allergic Diseases
Disclosures
 
James E. Gern, MD
WebMD
 
 
Introduction
Allergies and asthma in children are increasing in prevalence, and all signs
indicate that lifestyle and environmental factors greatly influence the
onset of these chronic disorders. There has been a lot of research on the
potential effects of exposure to pollutants and allergens that could
adversely affect lung development or function. In this discussion, potential
mechanisms for the onset of asthma are explored, with a slightly different
focus. Two of the speakers focus on early life: first the potential role of
stress in the perinatal period, and then how viral infections and other
environmental insults could modify and interfere with normal neurologic
development in the lungs. Although many cases of asthma start in early life,
asthma can begin at any age, and the final discussion addresses whether
infections with atypical bacteria can cause asthma.
 
Impact of Stress on Immune Development, Allergy, and Asthma
Rosalind Wright, MD, MPH, Assistant Professor of Medicine, Harvard Medical
School, Boston, Massachusetts, reviewed evidence that stress in early life
could adversely affect immune development, thereby promoting allergies and
asthma. There are a number of connections between stress-response systems
and immunity. Infancy may be a critical period for stress effects because
this is a period of rapid immunologic development.
 
Stress physiology is organized around 2 systems: the sympathetic
adrenomedullary system and the hypothalamic pituitary-adrenocortical system.
Both of these systems are regulated in the brain and are susceptible to
external stressors. Mechanisms by which stress can affect the immune system
are under study in a variety of animal models, including cholinergic excess,
adrenergic deficiency, oxidative stress, and glucocorticoid resistance.
Research on rats and in monkeys has provided insight into specific effects
during early life, and maternal involvement appears to be critical. For
example, research on early experiences in rodents has demonstrated that
disturbing the animals' nest in ways that enhance maternal behavior results
in stress-resilient offspring. In contrast, disturbing the nest in ways that
disorganize maternal behavior causes offspring that are subsequently
vulnerable to stress.
 
A number of studies have shown that early childhood events also have lasting
effects on immune development and even allergies and wheezing. Painful
events, such as vaccinations, elicit stress cortisol responses. Remarkably,
these responses can be buffered by comforting the child instead of allowing
unchecked crying. Chronic stress could have long-term effects on the immune
system. High maternal stress during infancy and preschool is associated with
elevated serum cortisol levels in preschoolers.[1] Moreover, infants of
mothers with high cortisol levels during pregnancy seem to have more
pronounced negative behaviors during relatively benign stressors, such as
bathing.[2]
 
There is evidence that the nervous system can affect some of the important
cells of allergic inflammation through the production of immunologically
active molecules, such as substance P. Dr. Wright and colleagues[3] have
conducted clinical studies providing evidence of a direct connection between
stress, wheezing in infancy, and allergy. First, perceived caregiver stress
was compared with the frequency of repeated wheeze in early infancy.[3] High
stress levels were associated with a significantly higher rate of recurrent
wheeze (relative risk, 1.6; 95% confidence interval, 1.5-1.9). Of interest,
maternal stress predicted wheeze, but wheeze did not predict maternal
stress.
 
In an additional study, Wright and colleagues[4] conducted a birth cohort
study to evaluate prospective relationships between maternal stress and the
children's immune development. Measures of immune development included serum
immunoglobulin (Ig)E levels and proliferative responses of PBMC to dust mite
allergen extract. Higher levels of maternal stress over time were associated
with higher IgE levels and increased proliferative responses to house dust
mites. Moreover, tumor necrosis factor-alpha responses to allergen were
enhanced in the context of high stress.
 
There is conclusive evidence that high stress affects immune responses, and
may in fact modify immune development if the exposure occurs during a
vulnerable stage in development. These changes, through a number of
potential mechanisms, can skew the immune system to increase the risk for
allergic sensitization and wheezing. Additional studies are needed to
incorporate measures of stress exposure and reactivity during early
childhood. This additional information could be of great value in
determining effects on immune development, allergy, and asthma.
 
Neural Development and Childhood Asthma
Giovanni Piedimonte, MD, from the Division of Pulmonary Medicine at
University of West Virginia University School of Medicine, Morgantown, West
Virginia, discussed the effects of viral infections and other stressors on
neural development in the lungs during early life. One of the themes of this
session was that early childhood, because of the rapid developmental changes
in the lungs as well as the immune system, is a time of greater
vulnerability to environmental insults. This general theme is also
applicable to pulmonary neural networks. Dr. Piedimonte's studies in rodents
and clinical studies in infancy both provide evidence that neural
development in the lungs is quite plastic at this age, and if this process
is disturbed, there could be long-term adverse effects on lung physiology.
 
The process of neural development in the lungs is under the control of a
number of cytokines, such as nerve growth factor (NGF) and its corresponding
receptor TrkA. These factors control the branching of nerves into the
developing lungs, and are downregulated with age. Extrinsic factors, such as
viral infections, affect this process. For example, NGF is strongly
upregulated during infections with respiratory syncytial virus (RSV). This
effect is modified by age; in the young rat, NGF concentrations double,
whereas there is relatively little change in older rats.
 
Dr. Piedimonte's group has found evidence of similar processes in infants
infected with RSV.[5] Samples of lower airway cells and fluid were obtained
from 31 infants who required mechanical ventilation, including 15 infants
with RSV bronchiolitis, 5 infants infected with other viruses, and 11
postsurgical patients without infection. Sensitive assays were used to
measure NGF in serum samples and bronchial lavage fluid and cells, and TrkA
was assessed by immunohistochemistry in airway cells. NGF was increased in
the cells of RSV-infected children compared with controls, and the TrkA
receptor was found only in samples from infected infants. Thus, the clinical
study of acutely infected infants verified a number of the predictions of
the rodent model.
 
Overexpression of NGF during RSV infections could have a number of
downstream inflammatory effects. For example, NGF binding to TrkA can lead
to the release of neurokinins, such as substance P, which have potent
inflammatory effects on a number of airway cells. These downstream effects
have many similarities to hyperalgesia during the healing phase that follows
an acute burn injury of the skin. Pharmacologic interruption of these
proinflammatory neural pathways could be useful in treating
infection-related airway obstruction and hyperresponsiveness, and perhaps
long-term airway dysfunction that sometimes follows an acute RSV infection.
 
Mycoplasma, Chlamydia, and the Onset of Asthma
Monica Kraft, MD, Head of Pulmonary Medicine, Duke University, Durham, North
Carolina, presented data from a 1992 series of reports by Hahn[6] and others
that suggested that some previously healthy individuals who contracted
Chlamydia respiratory infections went on to develop chronic wheezing and
asthma. This postinfectious wheezing often seemed to respond to directed
antibiotic therapy, although many of these medications are also known to
have anti-inflammatory properties, which made it difficult to assess the
true role of the infection. Dr. Kraft reviewed subsequent epidemiologic
studies of atypical bacterial infections and asthma, and then presented her
own studies designed to assess mechanisms and response to therapy.
 
Problems with diagnostic techniques for acute and chronic infections with
Mycoplasma and Chlamydia have hindered attempts to conduct epidemiologic
studies of these organisms and asthma. Regardless of these limitations
related to diagnosis, several studies provided some interesting data. Wark
and colleagues[7] evaluated 54 adult patients with asthma, and found that
38% of asthma exacerbations were associated with an increase in antibody
titers to Chlamydia pneumoniae. In a large study involving children, Nagy
and colleagues[9] performed isotype-specific serologic tests for C
pneumoniae, and compared these results with variations in mannose-binding
lectin (MBL), a complement component that is important in clearance of other
respiratory infections. Variant alleles in MBL have been associated with
increased susceptibility to other types of respiratory infections. These
investigators found that the isotype specificity of the anti-Chlamydia
antibody response varied with MBL variants; antibody responses suggestive of
chronic infection were found more often in association with the variants.
These findings suggested that defective host immune responses could promote
chronic Chlamydia infections and asthma. Likewise, several studies of
Mycoplasma infection suggested that this organism could also be found in
association with the onset of asthma in some individuals.
 
Interpretation of the epidemiologic studies is limited by the fact that
atypical bacteria are difficult to detect by culture and the lack of
diagnostic testing of lower airway specimens. After treatment of a severe
Mycoplasma infection in the lower airway of a young woman with
steroid-dependent asthma produced remarkable clinical relief of the
underlying asthma, Dr. Kraft conducted a study to specifically evaluate
lower airway physiology and the presence of Mycoplasma in asthma. Subjects
in this trial were asthmatics with stable disease for at least 3 months, and
lower airway biopsies were performed in all. Twenty-two of 55 asthmatics had
evidence of Mycoplasma in the lower airway vs only 4 of 20 normal controls.
Chlamydia was detectable in an additional 9 subjects.[8] Treatment with
clarithromycin for 6 weeks produced clinical improvement in forced
expiratory volume in 1 second only in the subjects with lower airway
Mycoplasma as detected by polymerase chain reaction (PCR). Finally, mast
cells were increased in the PCR-positive subjects. Of note, the serology for
Chlamydia and Mycoplasma did not correlate with the detection of these
organisms in the lower airway.
 
Mycoplasma and Chlamydia can cause chronic infection, and there is
compelling evidence to indicate that in susceptible individuals, chronic
infection is associated with persistent airway dysfunction, recurrent
wheezing, and asthma. Efforts to further define mechanisms and the
epidemiology of this association are under way, and may provide additional
options for the investigation and treatment of difficult-to-control asthma.
 
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